Synthesis of α‐Aryl and α‐Heteroaryl 4‐Silyloxy Piperidines via a One‐Pot Negishi Cross‐Coupling Approach

The direct α-arylation of a protected 4-hydroxy piperidine via a one-pot Negishi cross-coupling reaction is described. The methodology uses a single solvent, toluene, for the lithiation/transmetallation/Negishi sequence and 20 examples are presented. Of note, the high-yielding cross-coupling of a range of pharmaceutically relevant heteroaryl bromides is reported. The reactions show high levels of 2,4-cis-diastereoselectivity and further functionalizations are also described. Piperidine is the most common nitrogen heterocycle in approved drugs and our approach delivers such heterocycles via a direct diastereoselective α-functionalization of 4-substituted N-Boc piperidines; as such, the approach is ready to be utilized in the pharmaceutical industry.